Imeglimin Improved Plasma Glucose Levels in Patients With Latent Autoimmune Diabetes of Adults: Report of 2 Cases

Abstract Imeglimin has not been well studied as an oral agent for the treatment of latent autoimmune diabetes of adults (LADA). We treated 2 cases of LADA with imeglimin. The case 1 patient was originally diagnosed with type 2 diabetes (T2D) at age 50 years and was treated with sulfonylurea, biguanide, canagliflozin, imeglimin, and dulaglutide. Before imeglimin, his glycated hemoglobin A1c (HbA1c) change was 94.0 mmol/mol (8.6%) in November 2022, but it dropped to 71.0 mmol/mol (6.5%) in May 2023 after imeglimin was added. The case 2 patient was originally diagnosed with T2D when she was aged 48 years. She was treated with vildagliptin, biguanide, luseogliflozin, and imeglimin. Her HbA1c before imeglimin was 92.9 mmol/mol (8.5%) in January 2023, which decreased to 75.4 mmol/mol (6.9%) in July 2023 after imeglimin was added. Although imeglimin has not been approved for treating type 1 diabetes and LADA, adding imeglimin to the current medication was effective in improving and controlling the patients’ plasma glucose.


Introduction
Imeglimin is a novel oral agent for the treatment of type 2 diabetes (T2D).Imeglimin's mechanism of action has dual effects: (a) increased glucose-stimulated insulin secretion and preservation of β-cell mass; and (b) enhanced insulin action, including the potential for inhibiting hepatic glucose output and improving insulin signaling both in the liver and skeletal muscle [1].
Latent autoimmune diabetes of adults (LADA) is a form of diabetes mellitus (DM) with features of both type 1 diabetes (T1D) and T2D.In Japan, LADA is referred to as slowly progressive insulin-dependent type 1 DM (SPIDDM).The American Diabetes Association classifies LADA as T1D that evolves more slowly than the classic disease and does not recognize it as a specific type of DM, while the World Health Organization termed LADA as "slowly evolving immunerelated diabetes." LADA is a disease of adults and the Immunology for Diabetes Society (IDS) has specified 3 criteria for its diagnosis: 1. Age greater than 35 years 2. Positive autoantibodies to islet β cells 3. Insulin independence for at least the initial 6 months after initial diagnosis.
The use of oral agents such as imeglimin for treating LADA has not been thoroughly studied [2].We present 2 cases of LADA treated with imeglimin.
This study was performed in line with the principles of the Declaration of Helsinki.Approval was granted by the review board of Soleiyu Asahi Clinic (November 5, 2022/No.2023-C-1).

Case 1
In June 2023, an 81-year-old male patient (body height: 163.0 cm, body weight: 56.7 kg, body mass index [BMI]: 21.3) was transferred to our clinic to continue his DM treatment.His previous history was unremarkable.His mother was being treated for T2D and he was also originally diagnosed with T2D when he was aged 50 years.
Chest x-ray examination and electrocardiogram were normal.He had simple diabetic retinopathy and bilateral light numbness in the lower limbs due to diabetic neuropathy.

Case 2
In June 2023, a 55-year-old female patient (body height: 158.0 cm, body weight: 61.2 kg, BMI: 24.5) was also transferred to our clinic to continue her DM treatment.She had previously been treated for hypertension and hypercholesteremia using bisoprolol fumarate and rosuvastatin calcium, respectively.In her family, her daughter is being treated for T1D.She was diagnosed with T2D at age 48 years.
A chest x-ray examination and electrocardiogram revealed no abnormalities.She did not have diabetic neuropathy and retinopathy.

Case 1
The patient had never had diabetic ketoacidosis and had never been treated with insulin until today.A screening examination in our clinic revealed that his antiglutamic acid decarboxylase (GAD) antibody level was 14.3 U/mL (normal range <5.0 U/mL).According to the diagnosis criteria for LADA as described earlier, we rediagnosed his diabetes as LADA.

Case 2
The patient had no diabetic ketoacidosis and was never administered insulin.Screening examination in our clinic revealed that her anti-GAD antibody level was 111.5 U/mL (<5.0 U/mL).According to the diagnosis criteria for LADA as described earlier, we rediagnosed his diabetes as LADA.

Case 1
The patient was treated with sulfonylurea (5.0 mg/day), biguanide (1000 mg/day), canagliflozin (100 mg/day), imeglimin (2000mg/day), and dulaglutide.He received suggestions and advice regarding necessary diet and lifestyle modifications by a registered nurse, a registered dietician, and his physician when he visited our clinic.

Case 2
The patient was treated with vildagliptin (100 mg/day), biguanide (1000 mg/day), luseogliflozin (5 mg/day), and imeglimin (2000 mg/day).She received suggestions and advice regarding necessary diet and lifestyle modifications by a registered nurse, a registered dietician, and her physician when he visited our clinic.

Outcome and Follow-up
Case 1

Discussion
LADA is autoimmune diabetes that begins in adulthood and does not require insulin for glycemic control for at least the first 6 months after diagnosis [3].Although LADA shares genetic, immunologic, and metabolic features with both T1D and T2D, it has recently been reported to be less immunogenic than T1D [4].
Therapy that preserves pancreatic β-cell function is a top priority in the treatment of LADA, and insulin has been the treatment of choice.Studies have shown preserved pancreatic β-cell function, as evidenced by a sustained stimulated C-peptide response, normal HbA 1c levels, and a decrease in autoantibody concentrations [5].On the other hand, sulfonylureas are a poor choice for LADA because they deplete β cells of insulin, as evidenced by falling C-peptide levels, persistence of antibodies, and earlier progression to requiring insulin treatment.Although metformin may initially improve glycemic control in LADA patients with higher BMI, it cannot solely achieve the second and more important goal of preserving pancreatic β-cell function or delaying its destruction.Thiazolidinediones have anti-inflammatory effects on pancreatic β cells that can prolong their survival and be beneficial if used in the earlier stage of LADA.Dipeptidyl-peptidase 4 inhibitors have shown promise in preserving pancreatic β-cell function in LADA, either alone or in combination with insulin.A study using the glucagon-like peptide 1 receptor agonist dulaglutide found that LADA patients had lower HbA 1c levels and improved pancreatic β-cell function, with results comparable to T2D [6].Although the use of sodium and glucose cotransporter 2 inhibitors in LADA patients has not been well studied, they are not recommended due to reports of euglycemic ketoacidosis [7].Imeglimin has not been approved for the treatment of T1D and LADA and has not been well studied.However, based on its mechanism of action, imeglimin could be expected to preserve pancreatic β-cell function in LADA patients [1].
Although both patients were previously treated as having T2D, we rediagnosed them as LADA based on the IDS diagnosis criteria [3].However, there is a possibility that both cases could be T2D with positive GAD antibody [8].
Besides the addition of imeglimin, their medication was not changed but their HbA 1c level improved month to month after imeglimin was added.Hence, imeglimin significantly improved plasma glucose control in LADA patients.So far, the addition of imeglimin has had no adverse effect on either patient.

Learning Points
• LADA is a form of diabetes mellitus with features of both T1D and T2D.• Therapy that preserves pancreatic β-cell function is a top priority in the treatment of LADA.• Imeglimin is a novel oral agent for the treatment of T2D.
• The use of imeglimin for treating LADA has not been thoroughly studied.
• Imeglimin significantly improved plasma glucose control in LADA patients.Contributors S.O. is responsible for the patients' clinical care.S.O., K.O., J.O., and E.Y. contributed to the analysis of data and writing of the case report.All authors read and approved the final manuscript.